Method of dose controlled application of bone graft materials by weight

ABSTRACT

Methods of providing dose controlled application of bone graft materials are disclosed. In particular, methods for determining a target quantity of bone graft material for clinical application in order to ensure maximum clinical results are provided. These methods comprise determining the target weight of the material to be applied.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/957,773 filed Aug. 2, 2013, now U.S. Pat. No. 9,339,392, whichapplication claims priority to U.S. Provisional No. 61/678,756, filedAug. 2, 2012, and entitled “METHOD OF PROVIDING DOSE CONTROLLEDAPPLICATION OF BONE GRAFT MATERIAL,” the contents of which areincorporated by reference in their entirety.

FIELD

The present disclosure relates generally to bone graft materials andmethods of dose controlled application of such materials. Moreparticularly, the present disclosure relates to methods for determininga target quantity of bone graft material for clinical application inorder to ensure maximum clinical results.

BACKGROUND

The role of bone graft materials in clinical applications to aid thehealing of bone has been well documented over the years. Most bone graftmaterials that are currently available, however, have failed to deliverthe anticipated results necessary to make these materials a routinetherapeutic application in reconstructive surgery. Improved bone graftmaterials for forming bone tissue implants that can produce reliable andconsistent results are therefore still needed and desired.

In recent years intensive studies have been made on bone graft materialsin the hopes of identifying the key features necessary to produce anideal bone graft scaffold, as well as to proffer a theory of themechanism of action that results in successful bone tissue growth. Atleast one recent study has suggested that a successful bone tissuescaffold should consider the physicochemical properties, morphology anddegradation kinetics of the bone being treated. (“Bone tissueengineering: from bench to bedside”, Woodruff et al., Materials Today,15(10): 430-435 (2012)). According to the study, porosity is necessaryto allow vascularization, and the desired scaffold should have a porousinterconnected pore network with surface properties that are optimizedfor cell attachment, migration, proliferation and differentiation. Atthe same time, the scaffold should be biocompatible and allow flowtransport of nutrients and metabolic waste. Just as important is thescaffold's ability to provide a controllable rate of biodegradation tocompliment cell and/or tissue growth and maturation. Finally, theability to model and/or customize the external size and shape of thescaffold is to allow a customized fit for the individual patient is ofequal importance.

Woodruff, et. al. also suggested that the rate of degradation of thescaffold must be compatible with the rate of bone tissue formation,remodeling and maturation. Recent studies have demonstrated that initialbone tissue ingrowth does not equate to tissue maturation andremodeling. Accord to the study, most of the currently available bonegraft materials are formulated to degrade as soon as new tissue emerges,and at a faster rate than the new bone tissue is able to mature,resulting in less than desirable clinical outcomes.

Other researchers have emphasized different aspects as the core featuresof an ideal bone graft material. For example, many believe that thematerial's ability to provide adequate structural support or mechanicalintegrity for new cellular activity is the main factor to achievingclinical success, while others emphasize the role of porosity as the keyfeature. The roles of porosity, pore size and pore size distribution inpromoting revascularization, healing, and remodeling of bone have longbeen recognized as important contributing factors for successful bonegrafting implants. Many studies have suggested an ideal range ofporosities and pore size distributions for achieving bone graft success.However, as clinical results have shown, a biocompatible bone grafthaving the correct structure and mechanical integrity for new bonegrowth or having the requisite porosities and pore distributions alonedoes not guarantee a good clinical outcome. What is clear from thiscollective body of research is that the ideal bone graft implant shouldpossess a combination of structural and functional features that act insynergy to allow the bone graft implant to support the biologicalactivity and an effective mechanism of action as time progresses.

Currently available bone graft materials fall short of meeting theserequirements. That is, many bone graft materials tend to suffer from oneor more of the problems previously mentioned, while others may havedifferent, negatively associated complications or shortcomings. Oneexample of such a graft material is autograft material. Autograftmaterials have acceptable physical and biological properties and exhibitthe appropriate mechanical structure and integrity for bone growth.However, the use of autogenous bone requires the patient to undergomultiple or extended surgeries, consequently increasing the time thepatient is under anesthesia, and leading to considerable pain, increasedrisk of infection and other complications, and morbidity at the donorsite.

When it comes to synthetic bone graft substitutes, the most rapidlyexpanding category consists of products based on calcium sulfate,hydroxyapatite and tricalcium phosphate. Whether in the form ofinjectable cements, blocks or morsels, these materials have a proventrack record of being effective, safe bone graft substitutes forselected clinical applications. Recently, new materials such asbioactive glass (“BAG”) materials have become an increasingly viablealternative or supplement to natural bone-derived graft materials. Incomparison to autograft materials, these new synthetic materials havethe advantage of avoiding painful and inherently risky harvestingprocedures on patients. Also, the use of these synthetic, non-bonederived materials can reduce the risk of disease transmission. Likeautograft and allograft materials, these new artificial materials canserve as osteoconductive scaffolds that promote bone regrowth.Preferably, the graft material is resorbable and is eventually replacedwith new bone tissue.

Many artificial bone grafts available today comprise materials that haveproperties similar to natural bone, such as implants containing calciumphosphates. Exemplary calcium phosphate implants contain type-Bcarbonated hydroxyapatite whose implant in general may be described as(Ca₅(PO₄)_(3x)(CO₃)_(x)(OH)). Calcium phosphate ceramics have beenfabricated and implanted in mammals in various forms including, but notlimited to, shaped bodies and cements. Different stoichiometricimplants, such as hydroxyapatite (HA), tricalcium phosphate (TCP),tetracalcium phosphate (TTCP), and other calcium phosphate (CaP) saltsand minerals have all been employed in attempts to match theadaptability, biocompatibility, structure, and strength of natural bone.Although calcium phosphate based materials are widely accepted, theylack the ease of handling, flexibility and capacity to serve as a liquidcarrier/storage media necessary to be used in a wide array of clinicalapplications. Calcium phosphate materials are inherently rigid, and tofacilitate handling are generally provided as part of an admixture witha carrier material; such admixtures typically have an active calciumphosphate ingredient to carrier volume ratio of about 50:50, and mayhave a ratio as low as 10:90.

As previously mentioned, the roles of porosity, pore size and pore sizedistribution in promoting revascularization, healing, and remodeling ofbone have been recognized as important contributing factors forsuccessful bone grafting materials. Yet currently available bone graftmaterials still lack the requisite chemical and physical propertiesnecessary for an ideal graft material. For instance, currently availablegraft implants tend to resorb too quickly (e.g., within a few weeks),while some take too long (e.g., over years) to resorb due to theimplant's chemical composition and structure. For example, certainimplants made from hydroxyapatite tend to take too long to resorb, whileimplants made from calcium sulfate or β-TCP tend to resorb too quickly.Further, if the porosity of the implant is too high (e.g., around 90%),there may not be enough base material available. Conversely, if theporosity of the material is too low (e.g., 10%) then too much materialmust be resorbed, leading to longer resorption rates. In addition, theexcess material means there may not be enough room left in the residualgraft implant for cell infiltration. Other times, the graft implants maybe too soft, such that any kind of physical pressure exerted on themduring clinical usage causes them to lose the fluids retained by them.

Improved bone graft materials that provide the necessary biomaterial,structure and clinical handling necessary for optimal bone grafting havepreviously been disclosed by applicants in U.S. Patent ApplicationPublication No. 2011/0144764 entitled “BONE GRAFT MATERIAL”, U.S. PatentApplication Publication No. 2011/0144763 entitled “DYNAMIC BIOACTIVEBONE GRAFT MATERIAL HAVING AN ENGINEERED POROSITY”, U.S. PatentApplication Publication No. 2011/0140316 entitled “DYNAMIC BIOACTIVEBONE GRAFT MATERIAL AND METHODS FOR HANDLING”, U.S. patent applicationSer. No. 13/830,629 entitled “BIOACTIVE POROUS BONE GRAFT IMPLANTS”,U.S. patent application Ser. No. 13/830,763 entitled “BIOACTIVE POROUSBONE GRAFT COMPOSITIONS IN SYNTHETIC CONTAINMENT”, and U.S. patentapplication Ser. No. 13/830,851 entitled “BONE GRAFT IMPLANTS CONTAININGALLOGRAFT.”

These bone graft materials provide an improved mechanism of action forbone grafting by allowing the new tissue formation to be achievedthrough a physiologic process rather than merely from templating. Thesebone graft materials and resultant implants formed from these materialsare engineered with a combination of structural and functional featuresthat act in synergy to allow the bone graft implant to support cellproliferation and new tissue growth over time. The bone graft implantsserve as cellular scaffolds to provide the necessary porosity and poresize distribution to allow proper vascularization, optimized cellattachment, migration, proliferation, and differentiation. The bonegraft implants are formed of synthetic materials that are biocompatibleand offer the requisite mechanical integrity to support continued cellproliferation throughout the healing process. In addition, the bonegraft materials are formulated for improved clinical handling and alloweasy modeling and/or customization of the external size and shape toproduce a customized implant for the anatomic site.

While these improved graft materials are ideal for providing the manybeneficial advantages currently lacking in available graft materials,yet without the negative complications associated with other graftmaterials, they nevertheless pose a different, more unique challenge forthe user. Similar to many other compressible and/or expandable orpliable graft materials, including fiber-based bone graft materials, dueto their tremendous pliability and flexibility, the manner of handlingthese materials becomes as important as the composition of the materialsthemselves. More specifically, due to the pliable nature of certaincompressible and/or expandable or pliable graft materials, which may beeasily compressible and expandable, it is desirable to provide a mannerof consistently delivering a known quantity of fibrous material therebyproviding a final implantable device possessing the desired targetporosity. Thus, the ability to control the ultimate or final porosity ofthe fibrous materials becomes paramount. Inconsistent application of thefibrous material, which affects the ultimate porosity of the implant,may result in unpredictable and less desirable clinical outcomes.Accordingly, there exists a need for dosage control of these bone graftmaterials. Embodiments of the present disclosure address these and otherneeds.

SUMMARY

The natural process of tissue or wound healing is a dynamic,multi-dimensional cascade of bioactive events, with each successiveevent being dictated by the current physical environment (which isconstantly changing over time as healing progresses) as well as thecascade's previous events. Therefore, ideal bone graft materials andimplants formed from these materials need to be engineered with acombination of structural and functional features that act in synergy toallow the bone graft implant to support cell proliferation and newtissue growth over time. The implants need to provide the necessaryporosity and pore size distribution to allow proper vascularization,optimized cell attachment, migration, proliferation, anddifferentiation. Not only do these implants need to be biocompatible,but also offer the requisite mechanical integrity to support continuedcell proliferation throughout the healing process.

In order to meet the demands of this complex process, many bone graftmaterials are formulated to be moldable, or compressible and/orexpandable. These materials may exist in a pliable state, such as in anexpandable and/or compressible fibrous or granular network, foam, orotherwise. The ability to compress or expand the bone graft materialimproves clinical handling and allows easy modeling and/or customizationof the external size and shape of the implants to produce a customizedimplant for the anatomic site. However, the compressible and/orexpandable nature of the material also presents a unique challenge tothe user or clinician. Exactly how much material should be used toproduce the ultimate graft implant is determined by a number of factors,including the anatomical site to be treated, the size of the site, theshape of the site, in addition to the physicochemical properties of thegraft material such as its porosity and pore size distribution. Withoutspecific parameters guiding usage of the materials, the amount of actualgraft material comprising these implants could vary widely from user touser, and from one day to another. For instance, the same cliniciancould create a more dense fibrous implant for one patient one day, aless dense fibrous implant for another patient another day, simply bymaking a best-guess as to how much material to use, or by using thephysical constraints of the site to determine how much material will beneeded, depending on the user's preferences for packing the material,without taking heed to the actual physicochemical requirements of theimplant based on the actual site to be treated.

Accordingly, the present disclosure provides several embodiments ofmethods for ensuring that the correct quantity of bone graft material isused to produce the graft implant that is to be clinically applied.Methods of providing consistent, dose controlled application ofcompressible and/or expandable, pliable bone graft materials aredisclosed. In particular, methods for determining a target quantity ofbone graft material for clinical application of the material in order toensure maximum clinical results are disclosed. These methods comprisedetermining the target weight of the material to be applied.

The roles of porosity, pore size and pore size distribution in promotingrevascularization, healing, and remodeling of bone have long beenrecognized as important contributing factors for successful bonegrafting implants. Many studies have suggested an ideal range ofporosities and pore size distributions for achieving bone graft success.Several embodiments are disclosed for controlling the dosage or porosityof the bone graft material to achieve a desired dosage or porositysuitable for a particular defect.

In one embodiment, a method of treating a defect is provided. The methodcomprises providing a compressible and/or expandable, porous graftmaterial. In one example, the graft material may comprise fibers or afibrous network capable of compression and/or expansion (i.e., movementrelative to one another). In another example, the graft material may bea combination of fibers and particulate or granules. In still anotherexample, the bone graft material may comprise compressible and/orexpandable particulate or granules. Next, the target porosity value ofthe material is calculated. The target porosity value should bedetermined based on the bone defect. The total weight of the materialcan be calculated, and finally a quantity representing the determinedtarget weight of the graft material may be provided for implantation.The defect may be a bone defect, and the graft material may be bonegraft material.

In another embodiment, a method of preparing a graft implant forimplantation into a defect is provided. The method comprises providing acompressible and/or expandable, porous, graft material. Next, the targetporosity value of the material is calculated. The target porosity valueshould be determined based on the defect. The total weight of thematerial can be calculated, and finally a quantity representing thedetermined target weight of the graft material may be used to form theimplant. The defect may be a bone defect, and the graft material may bebone graft material.

In still another embodiment, a method of providing a graft material byweight is provided. The method comprises: determining a target porosityvalue for a graft implant for treating a defect; calculating a targetweight for the amount of graft material to be used for the defect; andproviding an amount of graft material representing the target weight ina sterile container. The graft material may be a bone graft material foruse in treating bone defects.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the disclosure. Additional features of thedisclosure will be set forth in part in the description which follows ormay be learned by practice of the disclosure.

DETAILED DESCRIPTION OF THE EMBODIMENTS

The standard method for healing natural tissue with synthetic materialshas been to provide a device having the microstructure andmacrostructure of the desired end product. Where the desired end productis cancellous bone, traditional bone grafts have been engineered tomimic the architecture of cancellous bone. Although this has been thecurrent standard for bone grafts, it does not take into account the factthat bone is a living tissue. Each bony trabeculae is constantlyundergoing active biologic remodeling in response to load, stress and/ordamage. In addition, cancellous and cortical bone can support a vastnetwork of vasculature. This network not only delivers nutrients tosustain the living environment surrounding bone, but also supports redblood cells and marrow required for basic biologic function. Therefore,merely providing a synthetic material with the same architecture that isnon-biologic is insufficient for optimal bone healing and bone health.Instead, what is required is a mechanism that can recreate the livingstructure of bone.

Traditional synthetics act as a cast, or template, for normal bonetissue to organize and form. Since these synthetics are not naturallyoccurring, eventually the casts or templates have to be resorbed toallow for normal bone to be developed. If these architectured syntheticsdo not resorb and do not allow proper bone healing, they simply becomeforeign bodies that are not only obstacles, but potentially detrimental,to bone healing. This phenomenon has been observed in many studies withslow resorbing or non-resorbing synthetics. Since these synthetics arejust chemically inert, non-biologic structures that only resemble bone,they behave as a mechanical block to normal bone healing anddevelopment.

With the understanding that bone is a living biologic tissue and thatinert structures will only impede bone healing, a different physiologicapproach is presented with the present invention. Healing is a phasicprocess starting with some initial reaction. Each phase builds on thereaction that occurred in the prior phase. Only after a cascade ofphases does the final development of the end product occur—new bonetissue. The traditional method has been to replace or somehow stimulatehealing by placing an inert final product as a catalyst to the healingprocess. This premature act certainly does not account for thephysiologic process of bone development and healing.

The physiologic process of bone healing can be broken down to threephases: (a) inflammation; (b) osteogenesis; and (c) remodeling.Inflammation is the first reaction to injury and a natural catalyst byproviding the chemotactic factors that will initiate the healingprocess. Osteogenesis is the next phase where osteoblasts respond andstart creating osteoid, the basic material of bone. Remodeling is thefinal phase in which osteoclasts and osteocytes then recreate thethree-dimensional architecture of bone.

In a normal tissue repair process, at the initial phase a fibrin clot ismade that provides a fibrous architecture for cells to adhere. This isthe cornerstone of all connective tissue healing. It is this fibrousarchitecture that allows for direct cell attachment and connectivitybetween cells. Ultimately, the goal is to stimulate cell proliferationand osteogenesis in the early healing phase and then allow forphysiologic remodeling to take place. Since the desired end product isliving tissue, the primary objective is to stimulate as much living boneas possible by enhancing the natural fiber network involved ininitiation and osteogenesis as well as angiogenesis. With theunderstanding that bone is a living biologic tissue and that inertstructures will only impede bone healing, a different physiologicapproach is presented with the present invention. Healing is a phasicprocess starting with some initial reaction. Each phase builds on thereaction that occurred in the prior phase. Only after a cascade ofphases does the final development of the end product occur—bone. Thetraditional method has been to replace or somehow stimulate healing byplacing an inert final product as a catalyst to the healing process.This premature act certainly does not account for the physiologicprocess of bone development and healing.

The physiologic process of bone healing can be broken down to threephases: (a) inflammation; (b) osteogenesis; and (c) remodeling.Inflammation is the first reaction to injury and a natural catalyst byproviding the chemotactic factors that will initiate the healingprocess. Osteogenesis is the next phase where osteoblasts respond andstart creating osteoid, the basic material of bone. Remodeling is thefinal phase in which osteoclasts and osteocytes then recreate thethree-dimensional architecture of bone.

In a normal tissue repair process, at the initial phase a fibrin clot ismade that provides a fibrous architecture for cells to adhere. This isthe cornerstone of all connective tissue healing. It is this fibrousarchitecture that allows for direct cell attachment and connectivitybetween cells. Ultimately, the goal is to stimulate cell proliferationand osteogenesis in the early healing phase and then allow forphysiologic remodeling to take place. Since the desired end product is aliving tissue and not an inert scaffold, the primary objective is tostimulate as much living bone as possible by enhancing the natural fibernetwork involved in initiation and osteogenesis.

The natural process of tissue or wound healing is a dynamic,multi-dimensional cascade of bioactive events, with each successiveevent being dictated by the current physical environment (which isconstantly changing over time as healing progresses) as well as thecascade's previous events. Therefore, ideal bone graft materials andimplants formed from these materials need to be engineered with acombination of structural and functional features that act in synergy toallow the bone graft implant to support cell proliferation and newtissue growth over time. The implants need to provide the necessaryporosity and pore size distribution to allow proper vascularization,optimized cell attachment, migration, proliferation, anddifferentiation. Not only do these implants need to be biocompatible,but also offer the requisite mechanical integrity to support continuedcell proliferation throughout the healing process.

In order to meet the demands of this complex process, many bone graftmaterials are formulated to be moldable, or compressible and/orexpandable. These materials may exist in a pliable state, such as in anexpandable and/or compressible fibrous or granular network, foam, orotherwise. The ability to compress or expand the bone graft materialimproves clinical handling and allows easy modeling and/or customizationof the external size and shape of the implants to produce a customizedimplant for the anatomic site.

As mentioned, improved bone graft materials and bone graft implantsformed from these materials have previously been disclosed in U.S.Patent Application Publication No. 2011/0144764 entitled “BONE GRAFTMATERIAL”, U.S. Patent Application Publication No. 2011/0144763 entitled“DYNAMIC BIOACTIVE BONE GRAFT MATERIAL HAVING AN ENGINEERED POROSITY”,U.S. Patent Application Publication No. 2011/0140316 entitled “DYNAMICBIOACTIVE BONE GRAFT MATERIAL AND METHODS FOR HANDLING”, U.S. patentapplication Ser. No. 13/830,629 entitled “BIOACTIVE POROUS BONE GRAFTIMPLANTS”, U.S. patent application Ser. No. 13/830,763 entitled“BIOACTIVE POROUS BONE GRAFT COMPOSITIONS IN SYNTHETIC CONTAINMENT”, andU.S. patent application Ser. No. 13/830,851 entitled “BONE GRAFTIMPLANTS CONTAINING ALLOGRAFT”, all of which are co-pending and co-ownedby applicants, the contents of which are incorporated herein byreference.

In some embodiments, these bone graft implants attempt to recapitulatethe normal physiologic healing process by presenting the fibrousstructure of the fibrin clot. Since these bioactive implants are bothosteoconductive as well as osteostimulative, the fibrous network willfurther enhance and accelerate bone induction. Further, the free-flowingnature of the bioactive fibrous matrix or scaffold allows for naturalinitiation and/or stimulation of bone formation rather than placing arigid template that may impede final formation as with current graftmaterials. The material can also be engineered to provide a chemicalreaction known to selectively stimulate osteoblast proliferation orother cellular phenotypes.

In addition, some of these bone graft materials are formulated to bemoldable, or compressible and/or expandable. The materials may exist ina pliable state, such as in an expandable and/or compressible fibrous orgranular network, foam, or otherwise. The ability to compress or expandthe bone graft material improves clinical handling and allows easymodeling and/or customization of the external size and shape of theimplants to produce a customized implant for the anatomic site.

While these improved graft materials are ideal for providing the manybeneficial advantages currently lacking in available graft materials(without the negative complications associated with other graftmaterials), they nevertheless pose a different, more unique challengefor the user. Like with many other pliable or moldable bone graftmaterials, due to the tremendous pliability and flexibility of thesematerials, what has become evident is that the manner of handlingfiber-based materials becomes as important as the composition of thematerials themselves. More specifically, due to the pliable nature ofthese graft materials, which may be easily compressible and/orexpandable, it is desirable to provide a manner of consistentlydelivering a known quantity of fibrous material having a known porositygradient as a final implant product. Thus, the ability to control theultimate or final porosity of the fibrous materials becomes paramount.Inconsistent application of the fibrous material, which affects theultimate porosity of the material, may result in unpredictable clinicaloutcomes.

For example, by way of background, freshly manufactured bioactive glassfibers of the kind previously disclosed by applicants are loosely packedand are approximately 95 to 97% porous, making the material air-like inconsistency, similar to cotton candy. These fibers can be easilycompressed and molded to various levels of porosity. The fibers may alsosettle over time and lose porosity due to gravitational forcescompressing the fibers together (i.e., deflation). Accordingly, for anygiven medical or clinical procedure, it is recommended that a specificfiber density range be established. Without a specific fiber densityrange, variability will exist in the amount of fibers used from onedefect site to another, and from one application to a differentapplication. Such variability could leave to unpredictable, and moreimportantly, undesirable clinical outcomes. For instance, under dosagecan lead to incomplete healing, while over dosage (i.e., overpacking thematerial into the defect site, for example) could impede the healingprocess. In an application where there is over dosage, the fibrous graftmaterial itself may actually stand in the way of the healing,potentially delaying or even compromising the healing process.

Accordingly, the present disclosure provides several embodiments ofmethods for ensuring that the correct quantity of bone graft material isused to produce the graft implant that is to be clinically applied.Methods of providing consistent, dose controlled application ofcompressible and/or expandable, pliable bone graft materials aredisclosed. In particular, methods for determining a target quantity ofbone graft material for clinical application in order to ensure maximumclinical results are disclosed. These methods comprise determining thetarget weight of the material to be applied.

In one embodiment, a method of treating a bone defect is provided. Themethod comprises providing a compressible and/or expandable bone graftmaterial. In one example, the bone graft material may comprise fiberscapable of movement relative to one another. In another example, thebone graft material may be a combination of fibers and particulate orgranules. In still another embodiment, the bone graft material maycomprise particulate or granules.

Next, the target porosity value of the implant is calculated. The targetporosity value should be determined based on the bone defect. The totalweight of the material can be calculated, and finally a quantityrepresenting the determined target weight of the bone graft material maybe provided for implantation.

In one application, the bone graft material may be packaged by weightinstead of volume. It is contemplated that surgical techniques wouldneed to specify the preferred weight of the graft material to be used.Such weight could be determined based on any number of factors,including the defect size and location. For example, a chart listing thedefect size for a specific location with corresponding recommended fiberdosage (by weight) may be provided for convenient reference. Oneexemplary dosage reference chart is provided below:

Defect Diameter Weight of material (grams/cm length of defect) 1 cm 0.5to 1.0 2 cm 2.0 to 4.0 3 cm 4.5 to 9.0

Based on the diameter of the defect to be treated, the weight of thefibrous graft material may be determined. During the procedure, theappropriately packaged weight of material would be applied to the defectas a manner of controlling the dosage or density of the material. Thevalues in the chart represent the fact that the relationship of fiberdosage to defect size may not always be a 1:1 ratio; accordingly, it isimportant to be able to provide the appropriate fiber density to allowfor enhanced bone healing.

In other embodiments, the weight of the fibrous graft material can bedetermined on any number of physical parameters of the bone defect, suchas dimension, size, geometry, volume, surface area, anatomic location,or extent of damage. The target weight of the material to be implantedmay be calculated using a mathematical algorithm that takes into accountthe physical parameter of the bone defect. Or, as previously mentioned,the target weight may be determined by referring to a chart wherebypredetermined weight ranges based on the physical parameter of the bonedefect have already been established.

In another embodiment, the fibrous bone graft material can be packagedby weight, with a prescribed use per unit volume of the defect. In thisexample, the volume of the defect may be considered the physicalparameter. For instance, a prescribed use of 0.5 to 1.0 grams of fibrousmaterial per cc of defect can be provided.

In still another embodiment, the fibrous bone graft material can beprovided in a pre-compressed state. In this pre-compressed state, thedensity may be such that the fibers are already settled, not in a stateof settling. For example, the fibrous graft material may bepre-compressed from 97% porosity to about 90% porosity so that thematerials may be able to hold their shape and will not deform furtherunless additional pressure is applied. The shape stable density maydepend at least in part upon the diameter of the fibers. The smaller thediameter of the fibers, the larger the shape stable density would needto be, as smaller fibers will tend to have lower mechanical strength andcan buckle under their own weight.

In yet another embodiment, the fibrous bone graft material may beprovided in packaging containers of known volume. The containers wouldbe filled with a known weight of the fibers so that a known density ofthe material is packaged for use.

In even still another embodiment, the fibrous bone graft material can bepre-compressed to a desired density and rolled into a sheet forpackaging and use.

It is understood that different challenges of healing exist fordifferent types of defects. These different challenges dictate the rateof absorption required of the graft material as well as the targetporosity. Take, for example, the different requirements for a spinalinterbody fusion, compared to a metaphyseal bone void fill, and comparedto a posterolateral fusion, using the same graft material. Each of thesebone healings takes place in a different anatomical region of the body,and therefore has different environmental constraints. One region couldhave a better connecting source of nutrients, while another region mayhave less access to nutrients. Accordingly, each location would requiredifferent characteristics of the same graft material to produce an idealclinical outcome. In other words, a one-size-fits-all scenario does notresult in the best chances of healing in these different bone healingexamples.

Starting with the same underlying graft material, in the case of thespinal interbody fusion, the natural environment surrounding this kindof defect (vertebral endplates) provides a good source of cells andnutrients for healing, thus relatively greater porosity is desired andconsequently less of the graft material (i.e., less density of material)needs to be used compared to a posterolateral fusion. In the case of theposterolateral fusion, relatively more material needs to be used becauseyou want a denser implant that is slower to resorb, hence less porosityis required with this type of fusion. A metaphyseal defect would requirethe least amount of material (i.e., least dense implant of all threegraft implants), since this is the least challenging of the three bonegraft applications discussed.

The embodiments of the present disclosure recognize that several factorsgo into the determination of the target porosity value. For example, thetarget porosity value may be determined according to a physicalparameter of the bone defect, such as dimension, size, geometry, volume,total surface area, anatomic location, or extent of damage. Based onthese factors, certain predetermined target values may be accorded tothe bone graft material for specific clinical usage. For example, takingthe above example of the three kinds of bone healing, it is possibleprovide a scale or reference chart with recommended dosages for aparticular bone graft material for a particular size defect and type offusion.

As shown below, an exemplary guide may be provided, such as for example,for a spinal interbody fusion using a 45S5 material, a type of bioactiveglass described in the applications cited above as well as in otherliterature. Taking into account the specific type of healing desired,the physical parameters of the defect, and the candidate material, itmay be possible to provide the clinician with a recommended guidance ordosage chart to ascertain the appropriate target porosity value for thefusion. One exemplary dosage reference chart is provided below:

Spinal Interbody Fusion using 45S5 Material Defect Volume TargetPorosity Value (+/−2.5%) 5 cc or less 80% 5-10 cc 75% 10 cc or more 70%This chart reflects the fact that, the smaller the defect size, theeasier or faster the healing process. Therefore porosity can be higherwith a smaller defect, as less material needs to be present to sustainthe physical infrastructure necessary to complete the healing process.It is contemplated that such a chart could be provided for a particulardefect of a specific anatomical region or location.

Once the target porosity value is established, the weight of the graftmaterial can be calculated using the material's density value. Byproviding a method of controlling dose application that is dependentupon the weight of the material, the present embodiments provide a verysimple, repeatable and reliable manner of calculating the amount ofgraft material needed for any particular defect. The following examplesserve to explain the rationale for the weight-based theory ofapplication of porous bone graft material of the present disclosure:

Example 1

A bone defect has a volume of 10 cc. The clinician has identified aparticular bone graft material, such as for example 45S5 bone graftmaterial (comprising bioactive glass fibers only) of the type previouslydisclosed by applicants, as having the appropriate physiochemicalproperties and structural integrity to heal this defect. The targetporosity can be determined, such as by referencing a dosage chartsimilar to the one above. The clinician then makes a calculation todetermine the weight of material to apply, as follows:

-   -   45S5 material density=2.7 grams/cc    -   Volume of defect=10 cc    -   Target porosity=70%

$\frac{{{Volume}\mspace{14mu}{occupied}\mspace{14mu}{by}\mspace{14mu}{material}} = {30\%\mspace{14mu}{or}\mspace{14mu} 3\mspace{14mu}{cc}}}{{{Weight}\mspace{14mu}{of}\mspace{14mu}{material}\mspace{14mu}{to}\mspace{14mu}{be}\mspace{14mu}{implanted}} = {{3 \times 2.7\mspace{14mu}\text{g/cc}} = {8.1\mspace{14mu}{grams}}}}$

In the previous example, the material comprised just fibers. However,the same principles and steps would apply equally if the materialcomprised a composite having some compressible and/or expandablecomponents and some non-compressible and/or non-expandable components.In other words, even if the material comprised fibers and particulatesor granules, the same weight would be needed for this material as wouldbe needed for a fiber-only material, assuming these two materials hadthe same density value of 2.7 grams/cc of volume of defect, and thedefects were the same. These examples show how the clinician can use asimple factor such as weight to determine the amount of material, ordosage of material, to be implanted into any particular defect. Thus,the methods disclosed are independent of the actual graft material, andcan be utilized so long as the density of the material is known.

In some cases, the graft material can be shipped and/or sold, orotherwise provided in an already pre-weighed form in accordance with therecommended dosage chart or guide. For example, using the example above,8.1 grams of 45S5 material can be packaged in a sterile 10 cc containeror vial. Thus, the material can be packaged and shipped in a pre-weighedform that is ready for use, such as for example, to fill a bone void,where the defect volume is 10 cc. A series of pre-weighed containers orvials corresponding to the recommended dosage chart above could beprovided to a clinician, so that the clinician could readily use apre-weighed 5 cc vial of material for a 5 cc or less volume defect, forinstance.

It is, of course, contemplated that the clinician could follow therecommended dosage of graft material as provided in the charts orreference guides discussed above, but is not restricted by theserecommendations. Depending on the patient's particular needs, theclinician could elect a more aggressive approach, or conversely a moreconservative approach. In some situations, the clinician may elect tomodify the treatment by using a biological agent in conjunction with thegraft material, for example. The biological agent may be one thataccelerates healing, such as for example, bone morphogenic protein,growth factors, stem cells, etc. In this aggressive approach, theclinician may therefore desire increased porosity in the graft, and makethe selection of dosage (i.e., amount of material by weight) based onthis desire for more porosity. Alternatively, should the clinician electa more conservative approach, he or she may desire a graft with a lowerporosity, or higher density, with a relatively slower healing rate. Thiskind of conservative treatment may be suitable for older patients, orfor smokers, for example, where the clinician does not want the graft toresorb too quickly. In these scenarios, the clinician could move up ordown one or more levels on the recommended dosage chart to determine thecorrect weight of the desired graft to be used.

The methods contemplated address the unmet need for a manner ofcontrolling dosage of fibrous, pliable and deformable bone graftmaterials irrespective of the composition of the materials. Although thepresent methods are described for use with applicants' previouslydisclosed fibrous bone graft materials, it is understood that themethods of the present invention are equally applicable to any graftmaterial that is compressible and/or expandable, or moldable. Further,the methods are not limited to bone graft materials for bone defects,and can be practiced with all types of graft materials that areexpandable or compressible, and for other defects, without limitation.

Other embodiments of the disclosure will be apparent to those skilled inthe art from consideration of the specification and practice of thedisclosure provided herein. It is intended that the specification andexamples be considered as exemplary only.

What is claimed is:
 1. A method of providing consistent, dose controlledapplication of a graft material to a defect, comprising: providing acompressible or expandable, porous graft material; determining a densityvalue of the graft material; calculating a target weight of a quantityof the graft material to be applied based on the determined densityvalue; and applying the quantity of graft material representing thetarget weight calculated to the defect.
 2. The method of claim 1,further comprising the step of forming a graft implant from the quantityof graft material representing the target weight calculated prior to theapplying step.
 3. The method of claim 1, wherein the step of calculatinga target weight comprises determining the porosity of the graftmaterial.
 4. The method of claim 3, wherein the step of calculating atarget weight comprises determining a percentage value of volumeoccupied by the graft material.
 5. The method of claim 4, furtherincluding the step of molding the graft material into a shapecorresponding to the determined percentage value of volume.
 6. Themethod of claim 1, wherein the graft material is in the form of fibers,particles, granules, clusters, or combinations thereof.
 7. The method ofclaim 1, wherein the graft material comprises silicone, calcium, sodium,or phosphate.
 8. The method of claim 1, wherein the defect is a bonedefect, and the graft material comprises bone graft material.
 9. Amethod of providing consistent, dose controlled application of acompressible or expandable, porous graft material to a defect,comprising: providing a dosage reference chart comprising: a physicalparameter of the defect; and a corresponding recommended attribute ofthe graft material, the attribute being either of a recommended dosageby weight or a target porosity value; performing a clinical evaluationto determine the physical parameter of the defect; referencing the chartto determine the required attribute of the graft material for thedetermined physical parameter of the defect; and applying a quantity ofgraft material having the required attribute to the defect.
 10. Themethod of claim 9, wherein the physical parameter comprises a dimension,size, geometry, volume, surface area, anatomic location, or extent ofdamage.
 11. The method of claim 9, wherein the dosage chart is for adefect in a specific anatomical location.
 12. The method of claim 9,further comprising the step of forming a graft implant from the quantityof graft material having the required attribute prior to the applyingstep.
 13. The method of claim 9, wherein the graft material is in theform of fibers, particles, granules, clusters, or combinations thereof.14. The method of claim 9, wherein the graft material comprisessilicone, calcium, sodium or phosphate.
 15. The method of claim 9,wherein the defect is a bone defect, and the graft material comprisesbone graft material.
 16. The method of claim 9, wherein the attribute isa recommended dosage by weight, and further including the step ofcalculating a target weight by determining the porosity of the graftmaterial and a density value of the graft material.
 17. The method ofclaim 16, wherein the step of calculating a target weight comprisesdetermining a percentage value of volume occupied by the graft material.18. The method of claim 9, wherein the graft material is in the form offibers, particles, granules, clusters, or combinations thereof.
 19. Themethod of claim 9, wherein the graft material comprises silicone,calcium, sodium, or phosphate.
 20. The method of claim 9, wherein thedefect is a bone defect, and the graft material comprises bone graftmaterial.
 21. A method of providing consistent, dose controlledapplication of a graft material to a defect, comprising: providing aseries of pre-sized containers of graft material, the containers havinga range of volumes corresponding to a range of defect volumes, whereinrecommended dosages by weight of the graft material corresponding to therange of defect volumes are provided in the respective containervolumes; performing a clinical evaluation to determine a volume of thedefect; selecting a pre-sized container of graft material based on thedetermined volume of the defect; and applying the graft material of theselected container to the defect.
 22. The method of claim 21, furthercomprising the step of forming a graft implant from the graft materialof the selected container prior to the applying step.
 23. The method ofclaim 21, wherein the graft material is in the form of fibers,particles, granules, clusters, or combinations thereof.
 24. The methodof claim 21, wherein the graft material comprises silicone, calcium,sodium or phosphate.
 25. The method of claim 21, wherein the defect is abone defect, and the graft material comprises bone graft material.